Isoproterenol-Induced Cardiac Hypertrophy: Modifications in Characteristics of β-Adrenergic Receptor, Adenylate Cyclase, and Ventricular Contraction*

Abstract

Several modifications in characteristics of the β- adrenergic receptor-adenylate cyclase system were observed in the cardiac hypertrophy of the rat produced by chronic isoproterenol treatment. These included 1) a decreased number of β- adrenergic receptors without changes in affinity when assayed by (-).[³H]dihydroalprenolol binding, 2) a decreased ability of 5′-guanylylimidodiphosphate to inhibit displacement by isoproterenol of the bound (-)-[³H]dihydroalprenolol, 3) a decreased sensitivity and magnitude of adenylate cyclase in heart homogenates to isoproterenol stimulation coupled with decreases in basal and NaF-stimulated enzyme activity, 4) a decreased responsiveness of the incubated heart minces to isoproterenol stimulation with respect to cAMP formation, and 5) a decreased contractile force development in ventricular strips in response to isoproterenol. All of the above alterations associated with the isoproterenol-induced cardiomegaly disappeared upon regressio n of hypertrophy. Light and electron microscopic studies revealed only minimal focal necrosis associated with some ultrastructural changes in the myocardium from rats with established or regressed cardiac hypertrophy. The present results clearly suggest that desensitization of the heart to the catecholamine resulting from chronic isoproterenol treatment of the rat is associated with alterations in the receptoradenylate cyclase system at the membrane level. These findings complement our earlier observations that the cAMP phosphodiesterase and stimulatory modulator of cGMP-dependent protein kinase are elevated in the cytosol and the cAMP-dependent protein kinase activation in response to isoproterenol stimulation in the incubated heart minces is decreased in isoproterenolinduced cardiac hypertrophy (Tse, J., N. L. Brackett, and J. F. Kuo, Biochim Biophys Ada 542: 399, 1978).